Endothelin-1 is a potent vasoconstrictor and binds to two receptors, ET-A and ET-B, which are variable expressed on endothelial cells, smooth muscle cells, and fibroblasts. Furthermore, endothelin-1 has been found to be released in vitro by scleroderma fibroblasts and could contribute to the development of dermal fibrosis in systemic sclerosis. Bosentan is a dual receptor antagonist, that competes with the binding of endothelin-1 to both receptors and has already been approved for the treatment of pulmonary arterial hypertension in Europe, the US, and some other countries. The purpose of this study is to evaluate the effect of bosentan treatment on skin fibrosis and functionality in patients with systemic sclerosis.

Further study details as provided by Heinrich-Heine University, Duesseldorf:

Primary Outcome Measures:

Measurable reduction of skin thickening using 20 MHz-ultrasound and the Rodnan Skin Score after treatment with study medication over 24 weeks in patients with systemic sclerosis.

Secondary Outcome Measures:

Effect of bosentan on hand functionality measured by SHAQ, UK-functional score, and fist closure as well as on nitrosylated serum protein levels in the plasma of patients with systemic scleroderma.

Estimated Enrollment:

10

Study Start Date:

June 2006

Study Completion Date:

May 2007

Detailed Description:

Systemic sclerosis (SSc) is a polymorphic disorder with an unknown cause characterized by fibrosis of the skin, blood vessels, and visceral organs. The degree of skin involvement is a very important outcome measure in patients with this disease. The pathogenesis of SSc involves immunologic mechanisms, vascular damage, and excessive accumulation of extracellular matrix component in the skin. One reason for these changes is meant to be an increased release of endothelin-1, a peptide which has vasoconstrictor effects and possesses mitogenic activity on cultured vascular smooth muscle cells and fibroblasts, cell types that are involved in SSc pathogenesis. Interestingly, endothelin-1 levels are raised in patients with SSc and Raynaud´s disease, particularly, in the subset of patients with diffuse cutaneous SSc who have widespread dermal sclerosis. However, skin fibrosis in SSc is a poorly studied, rare condition for which there are no approved therapies. Bosentan is a dual endothelin receptor antagonist, that competes with the binding of endothelin-1 to both receptors (ET-A and AT-B). It was recently shown to be effective in the treatment of idiopathic as well as pulmonary arterial hypertension (PAH) in SSc, but it has also been proved in two multicenter randomized prospective placebo-controlled double-blind studies in Europe and the US (RAPIDS-1 and RAPIDS-2) that there is a beneficial effect of bosentan in preventing digital ulcers in these patients. Furthermore,it has been suggested that bosentan has also a positive effect on skin fibrosis. In this study, skin fibrosis will be measured using 20-MHz-ultrasound, the Rodnan Skin Score, and investigation of the fist closure of each patient during treatment with bosentan over 24 weeks.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients with systemic sclerosis (diffuse SSc, limited SSc)

ACR criteria fulfilled

Current areas of skin fibrosis due to SSc

Women postmenopausal or negative pre-treatment pregnancy test as well as a reliable method of contraception during study treatment and for at least 3 months after study treatment termination

Signed informed consent

Exclusion Criteria:

Severe PAH or interstitial lung disease (WHO class III and IV)

Skin fibrosis and digital ulcers (DUs) due to conditions other than SSc

Systolic BP < 85 mmHg

Hemoglobin concentration < 75% of the lower limit of the normal range

AST and/or ALT values greater than 3 times the upper limit of normal

Moderate to severe hepatic impairment

Severe malabsorption, severe organ failure or any life threatening condition

Breast feeding

Treatment with any of the following drugs: glibenclamide (glyburide), cyclosporine A, and tacrolimus 1 week prior to study participation

Current treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction

Patient with conditions that prevent compliance with the protocol or adhering to therapy

Patient who received an investigational product within 1 month preceding screening

Known hypersensitivity to bosentan or any of the excipients

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00318175